A New Kind of Genomics, With an Eye on Ecosystems

Published: October 21, 2003

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Community genomics got its start in the 1980's, when scientists began sampling microbial DNA from the environment and studying a single gene that coded for part of the ribosome, the cell's protein-making machinery.

Virtually every creature on earth is thought to have this gene, though it has changed through evolution. So looking at it could tell scientists how many different types of microbes were present and into what broad categories they fell. But it did not tell them more about the way the bacteria functioned.

In the 1990's, scientists began to analyze larger fragments of DNA, looking for genes of interest. This was how Dr. DeLong found the photosynthetic bacteria and Diversa the enzyme to be used in making Lipitor.

Now, to get even more information, scientists are trying to determine the complete genome sequences of all the bacterial denizens of a community.

The technique they use is called shotgun sequencing, which was used by Celera in sequencing the human genome. Because gene-sequencing machines can handle only small stretches of DNA, the DNA to be sequenced is broken into random fragments. After the sequence of each fragment is determined, powerful computers assemble the pieces in the correct order by looking at overlapping sequences.

It is like shredding multiple copies of a book into tiny pieces and then trying to figure out the text.

But while this has been done for individual species, doing it for hundreds or thousands is expected to be much harder, like shredding and reconstructing multiple copies of multiple books. Dr. Venter says computer simulations indicate that it should be possible, at least for the Sargasso Sea.

Many scientists still doubt that. But success is already being seen on more narrow communities. Dr. Jill Banfield, professor of earth and planetary science at the University of California at Berkeley, is studying the microbes found 400 feet underground at Iron Mountain, an abandoned mine in Northern California. The microbes contribute to the highly acidic runoff that has made the mine a major hazardous waste site under the federal Superfund program.

Dr. Banfield, who is working with the Department of Energy's Joint Genome Institute in nearby Walnut Creek, says there are probably just seven different species in the sample, either bacteria or archaea, another type of microbe that tends to inhabit extreme environments. The full genomes of the two organisms have already been determined. ''As far as I know, it's the first time a genome has been recovered from a truly environmental sample,'' she said.

There are some obstacles to overcome before even trying to put the DNA fragments together into the correct order. Extracting DNA fragments from the environment can be difficult, particularly from soil, which contains acids that break down the genetic material. And one or two species may dominate in an environment, outnumbering other species by as much as 100,000 to 1. So the DNA fragments will be mainly from the dominant species.

''When somebody says they are going to sequence all the bacteria in a soil sample, well, that's rubbish,'' said Dr. Julian Davies, an emeritus professor of microbiology and immunology at the University of British Columbia.

Dr. Davies started a company to find new antibiotics by extracting genes from soil bacteria that could not be cultured in the laboratory. But antibiotic production is often governed by many genes, not just one, and it was impossible to extract DNA fragments large enough to contain all the necessary genes, he said.

Still, sampling techniques are improving. Diversa has a method, based on the relative density of DNA's chemical units, to prevent rarer species in a sample from being overlooked.

There is still debate about how valuable it will be to reconstruct the genomes of all members of a community. That alone will not necessarily tell which genes are active or how the bacteria interact with one another. ''What you get is a catalog,'' Dr. Davies said. ''You get unnamed organisms. The question is how can you tell what they do.''

But Dr. Steven R. Gill, a microbiologist at the Institute for Genomic Research, countered that if a creature's genetic blueprint was known, ''we can go back and reconstruct its metabolism.''

Besides providing clues about the roles organisms play, such information may pinpoint nutrients they need, allowing previously unculturable organisms to be grown in the laboratory. And once all the genes in an organism or community are known, it will be possible to make gene chips to study which genes are turned on or off as environmental conditions change.

Some scientists think ecosystem genome sequencing may eventually be used to monitor the health of environments or to predict environmental impacts. That could apply not only to the external environment but also to the ones inside people.

Dr. David A. Relman, an associate professor of medicine and microbiology at Stanford who is collaborating on the project to read the DNA of the bacteria in the human digestive tract, said changes in those bacterial communities contributed to diseases like colitis.

It may be possible to find patterns in the bacterial population that will predict when someone is about to get sick. The human gut metagenome project ''will be the first step in identifying these patterns,'' Dr. Relman said.

Photos: Dr. Edward F. DeLong of the Monterey Bay Aquarium Research Institute takes microbial plankton found in the bay and reads the community's DNA. (Photo by Peter DaSilva for The New York Times)(pg. F1); The full genomes of two microbes that Dr. Jill Banfield found in an abandoned mine in Northern California have already been determined. (Photo by Peter DaSilva for The New York Times)(pg. F6)